Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614, Poznań, Poland.
Unit of Biophysical Chemistry, Department of Physical Chemistry, Faculty of Chemistry, University of Lodz, Pomorska 165, Lodz, 90-236, Poland.
Eur J Med Chem. 2023 Aug 5;256:115450. doi: 10.1016/j.ejmech.2023.115450. Epub 2023 May 12.
Functionalization of alkyne (1) and azide (2) derivatives of geldanamycin (GDM) via dipolar cycloaddition CuAAC yielded 35 new congeners (3-37) with C(17)-triazole arms bearing caps of different nature (basic vs. acidic, hydrophilic vs. hydrophobic). Confrontation of biological data (anticancer activity vs. toxicity in normal cells) with lipophilicity (clogP), dissociation constants (K) of complexes with Hsp90 and binding modes to Hsp90 revealed SAR in specific subgroups of GDM derivatives. The most potent GDM congeners 14-16, bearing C(17)-triazole-benzyl-halogen arms exhibited the most optimal clogP values of 2.7-3.1 at favourable binding to Hsp90 (K at μM level). The anticancer activity of 14-16 (IC = 0.23-0.41 μM) is higher than those of GDM (IC = 0.58-0.64 μM) and actinomycin D (ActD, IC = 0.62-0.71 μM) in SKBR-3, SKOV-3 and PC-3 cell lines, with a comparable cytotoxicity in healthy cells. The relationship between structure and attractive anticancer potency (IC = 0.53-0.74 μM) is also observed for congeners with C(17)-triazole-saccharide or C(17)-triazole-unsaturated arms. In the former, the absolute configuration at C(4) (ᴅ-glucose vs. ᴅ-galactose) whereas in the latter the length of the unsaturated arm influences the cytotoxic effects due to different binding strength (K, ΔE) and modes with Hsp90. Among all triazole congeners of GDM that are biologically attractive and exhibit lower toxicity in normal cells than GDM and ActD, the derivative 22, bearing the C(17)-triazole-cinnamyl arm, shows the lowest K (Hsp90), optimal clogP = 2.82, the best pro-apoptotic properties in SKBR-3 and SKOV-3 and the best selectivity indices (SI). For the most potent GDM derivatives with C(17)-triazole arm, the docking studies have suggested the importance of the intermolecular stabilization between the arm and the D57 or Y61 of Hsp90.
通过点击化学 CuAAC 将格尔德霉素（GDM）的炔烃（1）和叠氮化物（2）衍生物官能化，得到了 35 个具有不同性质（碱性与酸性、亲水性与疏水性）帽的 C（17）-三唑臂的新同系物（3-37）。将生物数据（抗癌活性与正常细胞毒性）与亲脂性（clogP）、与 Hsp90 形成复合物的离解常数（K）和与 Hsp90 的结合模式进行对比，揭示了 GDM 衍生物特定亚组中的 SAR。具有 C（17）-三唑-苄基-卤代臂的最有效 GDM 同系物 14-16 的 clogP 值最理想，为 2.7-3.1，与 Hsp90 的结合性良好（K 值在 μM 水平）。在 SKBR-3、SKOV-3 和 PC-3 细胞系中，14-16（IC=0.23-0.41 μM）的抗癌活性高于 GDM（IC=0.58-0.64 μM）和放线菌素 D（ActD，IC=0.62-0.71 μM），在健康细胞中具有相当的细胞毒性。具有 C（17）-三唑-糖或 C（17）-三唑-不饱和臂的同系物也表现出结构与吸引力抗癌功效（IC=0.53-0.74 μM）之间的关系。在前一种情况下，C（4）处的绝对构型（ᴅ-葡萄糖与ᴅ-半乳糖），而在后一种情况下，不饱和臂的长度由于与 Hsp90 的不同结合强度（K、ΔE）和模式而影响细胞毒性作用。在所有具有生物吸引力且比 GDM 和 ActD 毒性更低的 GDM 三唑同系物中，具有 C（17）-三唑-肉桂基臂的衍生物 22 显示出最低的 K（Hsp90）、最佳 clogP=2.82、在 SKBR-3 和 SKOV-3 中最佳的促凋亡特性和最佳的选择性指数（SI）。对于具有 C（17）-三唑臂的最有效 GDM 衍生物，对接研究表明臂与 Hsp90 的 D57 或 Y61 之间的分子间稳定的重要性。
